Abstract

Myc has been known to control cell growth and proliferation through regulating thousands of genes, of which a substantial amount are involved in metabolism. We have previously shown that Myc increases ribosomal biogenesis, nucleotide metabolism, mitochondrial biogenesis, glycolysis and glutaminolysis in cancer cells. However, Myc's role in fatty acid metabolism is not well-documented, notwithstanding the expectation that Myc induction of cell growth must be accompanied by membrane biogenesis. Other studies have shown that fatty acids can be utilized as energy fuel by cancer cells or as building blocks for proliferation. The P493 human B cell line contains a tetracycline (Tet)-repressible human MYC transgene, permitting robust control of cell growth and proliferation through MYC. Having previously documented that Myc stimulates glucose and glutamine metabolism, we sought to determine whether Myc affects P493 use of fatty acids for oxidation and fatty acid synthesis. We found that resting P493 cells, in which ectopic MYC was off, can use labeled palmitate for respiration, while Myc activated P493 cells demonstrated an inability to oxidize palmitate. We also observe through microarray analysis and RT-PCR that Myc increases the levels of mRNAs for lipogenesis genes. Chromatin immunoprecipitation (ChIP) with an anti-Myc antibody documents that Myc binds to the promoters of lipogenesis genes. Moreover, immunoblot analyses with antibodies available for selected enzymes also indicate that Myc increases the protein levels of ACACA and FASN. Uniformly labeled 13C-glucose and 13C,15N-glutamine were found to be incorporated into lipids when Myc was induced in P493 cells. Cerulenin, an inhibitor of FASN, dramatically inhibits Myc-induced P493 cell proliferation. Similarly, TOFA-inhibition of ACACA suppresses P493 cell proliferation as well. Our data suggest that in P493 Burkitt lymphoma model cells, Myc inhibits fatty acid oxidation and upregulates fatty acid synthesis through transcription of target genes.